Efficacy and Safety of SPH3127 Tablet, a Novel Direct Renin Inhibitor, in Patients with Mild-to-Moderate Essential Hypertension: A Phase III Randomised Trial

OBJECTIVE: To evaluate the efficacy and safety of sitokiren (SPH3127) tablet in patients with mild-to-moderate essential hypertension in comparison to valsartan capsule. METHODS: This multicentre, randomised, double-blind, parallel Phase III trial was designed in 2 stages. In the 1st stage, eligible patients were randomised to receive 50 mg, 100 mg or 200 mg of SPH3127 tablet or 80 mg of valsartan capsule once daily (QD) for 12 consecutive weeks. In the 2nd stage, eligible patients were randomised to receive assigned dose of SPH3127 tablet based on the results from the 1st stage or valsartan 80 mg QD for 12 consecutive weeks. Primary outcome was the change from baseline in mean sitting diastolic blood pressure (msDBP) at Week 12. Safety outcome measures included any adverse events. Exploratory outcomes included plasma concentration of SPH3127, as well as the assessment of the correlation between SPH3127 exposure with the level of renin inhibition, clinical efficacy and occurrence of adverse events. RESULTS: The 1st stage enrolled 189 patients, of which 129 eligible patients were randomised. High plasma renin activity (PRA) inhibitory effect (83%) and the biggest reduction of msDBP at Week 12 from baseline (- 8.17 ± 5.90 mmHg) was detected in SPH3127 group at the dosage of 100 mg, which was determined for the subsequent stage 2 of this trial. The 2nd stage screened 1260 patients, of which 828 eligible patients were randomised to receive SPH3127 tablet 100 mg (N = 413) and valsartan capsule 80 mg (N = 415), QD. Main analysis based on the treatment policy strategy indicated 5.97 (0.41) mmHg [least-square mean (LSM) and standard error (SE)] of the msDBP changes at Week 12 from baseline in the SPH3127 and 6.32 (0.41) in valsartan groups, with inter-group difference of - 0.35 mmHg (95% CI: - 1.48, 0.78, p = 0.005). Main analysis based on hypothetical strategy showed 5.95 (0.41) mmHg of the msDBP changes at Week 12 from baseline in the SPH3127 and 6.31 (0.42) mmHg in valsartan groups, with inter-group difference of - 0.36 mmHg (95% CI: - 1.51, 0.78, p = 0.006). During the 12-week treatment period, 250 (61.1%) patients in SPH3127 group and 231 (56.2%) patients in valsartan group reported treatment emergent adverse events (TEAEs). Adverse drug reaction (ADR) was reported by 34 (8.3%) and 41 (10.0%) patients in SPH3127 and valsartan group, respectively. The serious adverse events (SAEs) reported by 10 patients were considered not related to the investigational drugs. Death was reported in 1 patient in the valsartan group due to myocardial infarction, which was considered not related to the study drug. CONCLUSIONS: Oral SPH3127 tablet 100 mg QD is effective and safe for adult patients with mild-to-moderate essential hypertension. TRIAL REGISTRATION: Clinicaltrials.gov Identifier number NCT05359068.